Beneficial effects of hepatic cyclooxygenase-2 expression against cholestatic injury after common bile duct ligation in mice.

Autor: Brea R; Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), CSIC-UAM, Madrid, Spain., Casanova N; Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), CSIC-UAM, Madrid, Spain., Alvarez-Lucena C; Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), CSIC-UAM, Madrid, Spain., Fuertes-Agudo M; Instituto de Biomedicina de Valencia (IBV), CSIC, Valencia, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain., Luque-Tevar M; Instituto de Biomedicina de Valencia (IBV), CSIC, Valencia, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain., Cucarella C; Instituto de Biomedicina de Valencia (IBV), CSIC, Valencia, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain., Capitani MC; Instituto de Fisiología Experimental (IFISE-CONICET), Rosario, Argentina., Marinochi MV; Instituto de Fisiología Experimental (IFISE-CONICET), Rosario, Argentina., Fusini ME; Cátedra de Histología y Embriología Humana-Fac. Cs. Médicas-UNR, Rosario, Argentina., Lahoz A; IIS-Hospital La Fe, Valencia, Spain., Nogueroles ML; IIS-Hospital La Fe, Valencia, Spain., Fraile J; Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), CSIC-UAM, Madrid, Spain., Ronco MT; Instituto de Fisiología Experimental (IFISE-CONICET), Rosario, Argentina., Boscá L; Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), CSIC-UAM, Madrid, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain., González-Rodríguez Á; Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), CSIC-UAM, Madrid, Spain.; Centro de Investigación Biomédica en Red de Diabetes y Enfermedades Metabólicas Asociadas (CIBERDEM), Madrid, Spain., García-Monzón C; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain.; Liver Research Unit, Hospital Universitario Santa Cristina, Instituto de Investigación Sanitaria Princesa, Madrid, Spain., Martín-Sanz P; Instituto de Investigaciones Biomédicas Sols-Morreale (IIBM), CSIC-UAM, Madrid, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain., Casado M; Instituto de Biomedicina de Valencia (IBV), CSIC, Valencia, Spain.; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain., Francés DE; Instituto de Fisiología Experimental (IFISE-CONICET), Rosario, Argentina.
Jazyk: angličtina
Zdroj: Liver international : official journal of the International Association for the Study of the Liver [Liver Int] 2024 Sep; Vol. 44 (9), pp. 2409-2423. Date of Electronic Publication: 2024 Jun 07.
DOI: 10.1111/liv.16004
Abstrakt: Background and Aims: Cyclooxygenase-2 (COX-2) is involved in different liver diseases, but little is known about the significance of COX-2 in cholestatic injury. This study was designed to elucidate the role of COX-2 expression in hepatocytes during the pathogenesis of obstructive cholestasis.
Methods: We used genetically modified mice constitutively expressing human COX-2 in hepatocytes. Transgenic mice (hCOX-2-Tg) and their wild-type (Wt) littermates were either subjected to a mid-abdominal laparotomy or common bile duct ligation (BDL) for 2 or 5 days. Then, we explored the mechanisms underlying the role of COX-2 and its derived prostaglandins in liver function, and the synthesis and excretion of bile acids (BA) in response to cholestatic liver injury.
Results: After BDL, hCOX-2-Tg mice showed lower grades of hepatic necrosis and inflammation than Wt mice, in part by a reduced hepatic neutrophil recruitment associated with lower mRNA levels of pro-inflammatory cytokines. Furthermore, hCOX-2-Tg mice displayed a differential metabolic pattern of BA synthesis that led to an improved clearance after BDL-induced accumulation. In addition, an enhanced response to the BDL-induced oxidative stress and hepatic apoptosis was observed. In vitro experiments using hepatic cells that stably express hCOX-2 confirmed the cytoprotective role of prostaglandin E 2 against BA toxicity.
Conclusions: Taken together, our data indicate that constitutive expression of COX-2 in hepatocytes ameliorates cholestatic liver injury in mice by reducing inflammation and cell damage and by modulating BA metabolism, pointing to a role for COX-2 as a defensive response against cholestasis-derived BA accumulation and injury.
(© 2024 The Author(s). Liver International published by John Wiley & Sons Ltd.)
Databáze: MEDLINE
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